Cardiovascular and renal effects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats

Abstract

Background Increased formation of advanced glycosylation end-products on body proteins is a consequence of aging and leads to exaggerated collagen cross-linking eventually increasing cardiovascular stiffness. This study reports our initial inquires into the cardiovascular and renal effects of a cross-link breaker (ALT-711) in aged spontaneously hypertensive rats (SHR). Methods and results The first experiment, in 45-week-old SHR, showed that (among four doses) the dose of 1 mg/kg/d of ALT-711 given for 4 months was most effective in reducing left ventricular and aortic mass indexes. ALT-711 also reduced left ventricular hydroxyproline concentration (5.8 ± 0.2 v 5.1 ± 0.3 mg/g in controls, P < .05); however, it did not affect systemic or regional hemodynamics. In older SHR, ALT-711 (1 mg/kg/d) reduced ( P < .05) systolic pressure (tail-cuff) (from 203 ± 3 mm Hg at outset to 187 ± 3 mm Hg at 8 weeks). Systolic pressure remained unchanged in placebo-treated rats. In addition, left ventricular index (3.09 ± 0.10 v 3.44 ± 0.05 mg/g) and aortic mass index (1.54 ± 0.04 v 1.74 ± 0.05 mg/mm) were reduced by ALT-711. In the third experiment, 1-year-old SHR were given vehicle or ALT-711 (1 mg/kg/d) or placebo until natural death. After 3 months, ALT-711 markedly reduced urinary protein excretion (74.5 ± 8.6 v 135.4 ± 11.8 mg/24 h). Echocardiographic studies, performed at the outset and after 3 and 6 months, revealed two changed indexes. Left ventricular end-diastolic diameter increased more in control than in ALT rats, whereas E-wave deceleration time decreased more in control than in ALT rats. Conclusions Therapy with ALT-711 exerted beneficial cardiovascular and renal effects in aged SHR, improving systolic pressure, left ventricular mass, geometry, and hydroxyproline content while reducing urinary protein excretion.